11beta, 12beta-epoxy and 12alpha-bromo steroids of the pregnane series and their method of preparation



113,12B-EPOXY AND IZa-BROMO STEROIDS'OF THE PREGNANE SERIES AND THEIR METH- OD OF PREPARATION Josef Fried, New Brunswick, and Patrick A. Diassi, Westfield, N.J., assignors to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Filed June 21, 1957, Ser. No. 667,289 13 Claims. (Cl. 269-39145) This invention relates to the synthesis of valuable steroids; and has forits object the'provision of i (I) an" advantageous process of preparing steroidsof-the pregnene series having a IZa-halogeh substituent'and" an 1115- v hydroxy substituent, and of (II-)I certain steroidsiuseful in the preparation of these phy'siologicallyactive steroid 'nane-hJlQZO-triol intermediate, and (b) oxidizing the resultant 115,12B-epoXypregnane-30:,20-di0l to 11,8,126- epoxypregnane-3,20-dione, a known intermediate in the preparation of IZbc-hfilO-l 1 fl-hydroxy progesterones 11 see the application of HerzetaL, Serial Nor-519E682, 1filed' July 1, 1955).

This series of steps may be represented by the following schematic analysis:

I R=CH3CO O C-OH t5 egg c Q 2,973,377. r fi Patented Feb.=28 1961 The new compounds of this invention 'are'represented by the Formulae IV and V, wherein the 20-'hydroxy' group can be in either the alpha orbeta position.

To prepare the 11/3,1ZB-ep Xypregnane-3a,20-diols-ofthis invention an ester of 12tX-bI'OI1'10pIegH3I1e-306-01-11,' 20-dione (e.g., an ester with a hydrocarbon carboxy1ic-- acid of less than' ten-carbon atoms*as exemplifiedby the lower alkanoic acids) can be reduced by treatment with a reducing agent such as a complex metal hydride (e.g. lithium-borohydride) and the resultingmixture con taining the 12a-brom0pregnane-3a,11,8,20-triols and their;- 3-esters can then be hydrolyzed and dehydrobrominated by treatment with a basic reagent, such as potassium hydroxideor a salt of a strongt base and; weak acid (e.g. potassium carbonate), to the 1l/3,12,B-epoxypreg-- HtlH6-30t,20-dl0l derivatives.

The 11,8,12/3-epoxypregnane-3a;20-diolscan" also be prepared by treating 12a-bromopregnane-3uol-l1,20 dione with a reducing agentsuch-as a'complex metal hydride (e.g. lithium borohydride) whereby a mixture-of the l2d-bromopregnane-3a,l1 3,20-triols v and 1113 ep'0Xypregnane-3a,20-diols is formed. The IZu-bIOmO" derivatives can thenbeconvertedin sit-u to the epoxyderivatives by treatment wit-h-a basic reagent; such-as potassium hydroxide or a saltofa strongbaseandweakb acid-. ezgt; potassium carbonate):

The conversion of 12a-bromopregnane wolfl1320- dione to a mixture of 12u-bromopregnane-3a,11B,20,8- triol and 1lfl,12fi-epoxypregnane-3a,20[i-diol can also be done stepwise by first reducing the IZki-bromopregnane- CH; HO-H a 3eol-11,20-dione to lZa-bromopregnane-S:,205-di0l-11- one by treatment with sodium borohydride at a low temperature (e.g. 0 C. or less) and then reacting the latter with a complex metalhydride such as lithium borohydride and if desired, a hydrolyzing agent as described hereinbefore.

The 11,8,IZfi-epoxypregnane-Ba,20-diols are then oxidized, as by treatment with a hexavalent chromium compound (eg. chromic anhydride), the reaction preferably being conducted at a low temperature (eg. 0 C. or less) employing a dilute solution of the chromic compound in an organic solvent, such as acetone. The reaction yields 11p,12,8-epoXypregnane-3,20-dione which then can be converted to the 12a-halo-1lfl-hydroxyprogesterones as described in said application, Serial No. 519,682.

11,9,12 8-epoxypregnane-3,20-dione can also be converted to the IZa-halo-lIB-hydroxyprogesterones via the new intermediate 4fi,12a-dibromopregnane-11B-ol-3,20- dione, which is formed by treatment of 11,53,12y3-epoxypregnane-3,20-dione with hydrogen bromide and bromine in an acid solution.

The 4 8,12u-dibromopregnane-11,B-ol-3,20-dione is then heated with a lithium halide (e.g. lithium bromide and lithium chloride) in a solvent of high dielectric constant, such as dimethyl formamide, whereby the corresponding 12a-halo-1lfl-hydroxyprogesterone (e.g., 12abromo-l lfl-hydroxyprogesterone and IZa-ChlOIO-llfl-hY- droxyprogesterone) is formed.

This series of steps can be represented by the following schematic analysis:

The following examples illustrate the invention (all temperatures being in centigrade). The first three examples disclose alternative processes for preparing the 11,6,12i3-epoxypregnane-3a,20-diols (V) EXAMPLE 1 (a) 12a-bmm0pregnane-3m-0l-I1,20-di0ne (II) A suspension of 12a-brom0pregnane-3a-ol-l1,20-dione 3-acetate (I) (10.0 g.) in 0.275 N perchloric acid in methanol (200 ml.) is stirred at room temperature for 63 hours. The clear solution is then adjusted to pH 6.0 with 5% NaHCO diluted with water (200 ml.) and extracted with chloroform (3 x 300 ml.). The combined chloroform extracts are washed with water (500 ml.), and evaporated to dryness in vacuo. Crystallization from acetone-hexaue gives the pure 304-01 (11) about (7.19 g.) melting at about 158160; [011 +9.43 (c., 0.525 in CHCl Ami? 2.95, 5.85, 5.90

Analysis.-Calcd. for C H O Br (411.38): C, 61.31; H, 7.59; Br, 19.40. Found: C, 61.72; H, 7.44; Br, 19.49.

(b) 115,1 Zfl-epoxypregltane-3a,20-diol from 12ozbrom0pregnane-3a-0l-11 ,2 O-dione (ll To a stirred solution of lithium borohydride (256 mg.) in dry tetrahydrofuran (30 ml.) cooled to 0 by an icesalt bath, a solution of l2a-bromopregnane-3a-ol-l1,20- dione (486 mg.) in dry tetrahydrofuran (20 ml.) is added dropwise. The mixture is stirred at 0 for 5 hours and the excess lithium borohydride is then decomposed by the cautious addition of 10% acetic acid (approximately 5 ml. required). The solution is diluted with water (20 ml.), extracted with chloroform (3 x 58 ml.) and the combined chloroform extracts washed with water ml.) and evaporated to dryness in vacuo.

The residue consisting of a mixture of 12a-bromopregnane-3u-llfl,20oi-triol (IVa), 12a-bromopregnane-3u,- l1B,20p-tri0l (IVb), 11[3,l2p-epoXypregnane-304,20a-di0l (Va), and 11B,12fl-epoxypregnane-3mZOfl-diol (Vb) is redissolved in 40 ml. methanol and 10% K CO (4 ml.) is added dropwise with stirring. After 20 minutes the solution is neutralized with 10% acetic acid, water (40 ml.) is added and the methanol removed in vacuo. The residue is extracted with chloroform (2 x 50 ml.) and the chloroform extracts are evaporated to dryness. The residue is crystallized from acetone-hexane to give 11B,12B-epoxypregnane-3a,2OB-diol (Vb) about (298 mg.) melting at 195-496; M1 +36.7 (c., 0.464 in ethanol);

Analysis.--Calcd. for C l-1 0 (334.48): C, 75.40; H, 10.24. Found: C, 75.30; H, 10.00.

' Concentration of the mother liquors gives 1113,125- epoxypregnane-3a,20a-diol (Va) about (8 mg.) melting at 218-220 C.; [M +47.1 (MeOH);

Analysia-Calculated for C21H34O3 (334.48): c, 75.40; H, 10.24. Found: c, 75.33; a, 9.83.

EXAMPLE 2 From l2a-bromopregnane-3oz-0l-II,ZO-dione 3- acctate (1) via lithium borohydride reduction To a solution of lithium borohydride (400 mg.) in dry tetrahydrofuran (25 ml.) cooled in an ice bath, a solution of 12a-bromopregnane-3u-ol-l1,20-dione 3-acetate (1.00 g.) in dry tetrahydrofuran is added dropwise, with stirring. After stirring at 0 for 5 hours the reaction is completed as described in Example 1b for the 3-01 to give 1lfl,l2 3-epoxypregnane-3a, 20p-diol (Vb) about (356 mg), M.P. about 196-198 and UBJZB-epoxypregnane-3a,20m-diol (Va) about (12 mg.) M.P. at 218- 220.

The residue obtained by evaporating the mother liquor of crystallization to dryness in vacuo contains residual amounts of the above mentioned products as well as 11,9, 12e-epoxypregnane-3a,20fi-diol 3-acetate and 11 6,12 6- epoxypregnane-3u,20a-diol B-acetate. This is dissolved in methanol (30 ml.), 10% potassium carbonate (10 ml.) is added and the mixture is left at room temperature overnight. The solution is then neutralized with 10% acetic acid and the methanol removed in vacuo. The residue is distributed between chloroform (30 ml.) and water (30 ml.), the chloroform layer is separated and the solvent evaporated to dryness. An additional mg. of 1118,12fi-epoxypregnane-3u,20;3-diol is obtained from the residue by crystallization from acetone-hexane.

EXAMPLE 3 From 12u-bromopregnane-3 -ol-11,20-dione (I I) via sodium borohydride followed by lithium borohydride reduction To a solution of sodium borohydride (309) mg.) in tetrahydrofuran (25 ml.) and water (5 ml.) a solution of 12a-bromopregnane-3a-ol-11,20-dione (605 mg.) in tetrahydrofuran ml.) is added and the resulting mixture is left at room temperature for 5. hours. The excess reducing agent is decomposed with 10% acetic acid and the tetrahydrofuran is removed in vacuo. The residue is extracted with chloroform, the chloroform phase is washed with water and evaporated to dryness in vacuo. The residue is crystallized from aqueous methanol to give 12a-b-romopregnane-3a,20fi-diol-1l-one (III) 300 mg.) melting at 237-2375 [a] -33.0 (ethanol);

Analysis.Calcd. for C H O Br (413.39): C, 61.01; H, 8.04; Br, 19.33. Found: C, 61.42; H, 8.10; Br, 19.35.

Isopropanol may be substituted as solvent in place of the tetrahydrofuran water mixture. Under these conditions the reaction is run at room temperature for 21 hours.

Further reduction of 1Za-bromopregnane-Sa,20;3-diolll-one by lithium borohydride in tetrahydrofuran as described in Example 1b followed by epoxidation with potassium carbonate gives 11B,12B-epoxypregnane-3a, 205-dio1 (Vb).

EXAMPLE 4 11,8,12,3-epoxypregnane-3,ZO-dione V1) To a stirred solution of 1.0 g. of 115,125-epoxypregnane 30:,20fi-di0l (Vb) in 100 ml. of acetone cooled in an ice bath, a solution containing chromic anhydride (430 mg), sulfuric acid (689 mg.) and water (2.3 g.) in 20 ml. acetone is added dropwise. After 20 minutes the excess oxidizingagent is reduced with ethanol and the precipitated chromic sulfate is filtered and washed with acetone. The filtrate is diluted with water (100 ml.) and the acetone removed in vacuo. The residue is extracted with chloroform (2 x 100 ml.) and the combined chloroform extract are washed with water (2 X 100 ml.) and evaporated to dryness in vacuo. Crystallization from acetone-hexane gives platelets of 115,125- epoxypregnane-3,20-dione (VI) about (583 mg.) melting at about 143-144". The infrared spectrum of this compound is identical with that of an authentic sample.

In like manner 11B,l2fi-epoxypregnane-3a,20u-diol (Va) can be oxidized to 11,3,12/8-epoxypregnane-3,20- dione.

EXAMPLE 5 413,12a-dibromopregnane-l1B-0l-3,20-dione VII) To a solution of 213 mg. of 115,12B-epoxypregnane- 3,20-dione in ml. of glacial acetic acid is added 0.2 ml. of 11% hydrogen bromide in acetic acid and shortly thereafter 1.13 ml. of a solution containing bromine (98.2 mg./ml.) in glacial acetic acid is added dropwise with stirring. After the addition is completed, the reaction is allowed to proceed for 10 minutes at room temperature. 3 ml. of 10% sodium acetate solution is then added until the straw-yellow color disappears. The acetic acid solution is concentrated in vacuo, the concentrate taken up in 25 ml. of chloroform, washed with water (2 x 25 ml.), dilute sodium bicarbonate, and again with water, dried over sodium sulfate and the solvent evaporated to dryness in vacuo. The residue is crystallized from acetone-hexane to give pure 45,12a-dibromopregnane-11fl-ol-3,20-dione (VII) (about. 218 mg.), M.P. about 212-214 (dec.);

he? .96, 5.78, 5.93,. [a] +80 (c., 1.24 in chloroform).

-A'nalysis.-+Calcd. for C2 H O Br' (490.28): C, 51.45; H, 6.16; Br. 32.60; Found: C, 51.19; H, 6.31; Br. 33:16.

In place of acetic acid alone as solvent for the bromination, chloroform may be added up to a 1:1 ratio of the two solvents;

EXAMPLE 6 12d-br'0in'o-1 I ,B-hydmxy progesterone VI 11a Its infrared spectrum is identical with that of an authentic sample.

EXAMPLE 7 1 2u-chl0r0-1 1 B-hydroxyprogesterone (VIII [2) A solution of 30 mg. of 4p,12a-dibromopregnane-11(3- ol-3,20-dione and 79 mg. of lithium chloride in 1.5 ml. of dimethylformamide is heated on the steam bath for two hours. The solution is then cooled, diluted with water and the resulting crystals filtered off and washed with water. The dried crystals after recrystallization from acetone-hexane melt at 230-231. The infrared spectrum is identical with that of an authentic sample of 12a-chloro-l lfi-hydroxyprogesterone.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. 12a-bromopregnane-3a,11,8,20-triol.

2. 413,12a-dibromopregnane-1 1 fi-ol-3,20-dione.

3. A process for preparing 12a-bromopregnane-3a,- 115,2013-triol, which comprises reducing 12a-bromopregnane-3a,20B-diol-1l-one with lithium borohydride.

4. A process for preparing 115,12B-epoxypregnane- 3,20-dione, which comprises' treating 11,8,12B-epoxypregnane-3a,20-diol with chromic anhydride and recovering the l1,8,12fl-epoxypregnane-3,20-dione formed.

5. A process for preparing 4p,12u-dibromopregnane- 11fl-ol-3,20-dione, which comprises treating 11,8,12B- epoxypregnane-3,20-dione with hydrogen bromide and bromine in an acidic medium.

6. A process for preparing a 12a-halo-11,8-hydroxyprogesterone wherein the halo radical is selected from the group consisting of bromo and chloro, which comprises treating 4fl,l2a-dibromopregnane-l1B-ol-3,20-dione with a lithium halide selected from the group consisting of lithium bromide and lithium chloride in an organic solvent of high dielectric constant.

7. A process for preparing l2a-bromo-llfi-hydroxyprogesterone, which comprises treating 4p,12a-dibromopregnane-l1,6-ol-3,20-dione with lithium bromide in dimethyl formamide.

8. A process for preparing Ila-ChlOrO-llfi-hYdI'OXY- progesterone which comprises treating 45,12a-dibr0mopregnane-l1B-ol-3,20-dione with lithium chloride in dimethyl formamide.

9. A process for preparing an 115,125-cpoxypregnane- 3a,20-diol which comprises treating a compound selected from the group consisting of 12a-bromopregnane-3a-ol-.

11. A process for preparing 12a-bromopregnane-- 7 i 8 3u,11}8,20-triols, which comprises reducing 12a-bromo- 3a,20B-di01 which comprises treating 12a-bromopregnanepregnane-3a-ol-11,20-dione by treatment with lithium 3a,20p-diol-il-one with lithium borohydride and dehydroborohydride and recovering the IZa-brOmOPIegHaBB- brominating the resulting compound by treatment with a 3a,1l 8,20-triols formed. 7 basic reagent,

12. A process for preparing an 11B,12B-epoxypreguane- 5 3a,20-diol which comprises treating a compound selected References Cited in the file of this patent from the group consisting of 12m-bromopregnane-3a-ol- 11,20-dione and the 3-esters thereof with lithium boro- UNITED STATES PATENTS hydride and dehydrobrorninating the resulting compound 2,403,683 Reichstein July 9, 1946 by treatment with a basic reagent. 10 2,447,325 Gallagher Aug. 17, 1948 13. A process for preparing 1119,125-epoxypregnane- 2,776,302 Ruzicka et a! Jan. 1, 1957 

2. 4B,12A-DIBROMOPREGNANE-11B-OL-3,20-DIONE. 